title: Frequent and simultaneous epigenetic inactivation of TP53 pathway genes in acute lymphoblastic leukemia.
abstract: Aberrant DNA methylation is one of the most frequent alterations in patients with Acute Lymphoblastic Leukemia (ALL). Using methylation bead arrays we analyzed the methylation status of 807 genes implicated in cancer in a group of ALL samples at diagnosis (n = 48). We found that 154 genes were methylated in more than 10% of ALL samples. Interestingly, the expression of 13 genes implicated in the TP53 pathway was downregulated by hypermethylation. Direct or indirect activation of TP53 pathway with 5-aza-2'-deoxycitidine, Curcumin or Nutlin-3 induced an increase in apoptosis of ALL cells. The results obtained with the initial group of 48 patients was validated retrospectively in a second cohort of 200 newly diagnosed ALL patients. Methylation of at least 1 of the 13 genes implicated in the TP53 pathway was observed in 78% of the patients, which significantly correlated with a higher relapse (p = 0.001) and mortality (p<0.001) rate being an independent prognostic factor for disease-free survival (DFS) (p = 0.006) and overall survival (OS) (p = 0.005) in the multivariate analysis. All these findings indicate that TP53 pathway is altered by epigenetic mechanisms in the majority of ALL patients and correlates with prognosis. Treatments with compounds that may reverse the epigenetic abnormalities or activate directly the p53 pathway represent a new therapeutic alternative for patients with ALL.
authors.affiliation: Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Vilas-Zornoza
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.forename: Vanesa
authors.initials: V
authors.lastname: Martín-Palanco
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Martín-Subero
authors.forename: Edurne
authors.initials: E
authors.lastname: San José-Eneriz
authors.forename: Leire
authors.initials: L
authors.lastname: Garate
authors.forename: Sara
authors.initials: S
authors.lastname: Álvarez
authors.forename: Estíbaliz
authors.initials: E
authors.lastname: Miranda
authors.forename: Paula
authors.initials: P
authors.lastname: Rodríguez-Otero
authors.forename: José
authors.initials: J
authors.lastname: Rifón
authors.forename: Antonio
authors.initials: A
authors.lastname: Torres
authors.forename: María José
authors.initials: MJ
authors.lastname: Calasanz
authors.forename: Juan
authors.initials: J
authors.lastname: Cruz Cigudosa
authors.forename: José
authors.initials: J
authors.lastname: Román-Gómez
authors.forename: Felipe
authors.initials: F
authors.lastname: Prósper
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D044127:Epigenesis, Genetic / Q000502:physiology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D005787:Gene Frequency; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53